rs145847114

Variant names:

• chr19-49190772-G-A
• rs145847114
• NM_017636.4:c.2209G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017636.4(TRPM4):​c.2209G>A​(p.Gly737Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,062 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (19 hom.)
• Consequence: TRPM4 NM_017636.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004656
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.841
• Publications: 10 publications found

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 6

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive familial heart block type IB

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069471).
• BP6: Variant 19-49190772-G-A is Benign according to our data. Variant chr19-49190772-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468934.
• BS2: High AC in GnomAd4 at 286 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	NM_017636.4	MANE Select	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.1864G>A	p.Gly622Arg	missense splice_region	Exon 14 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 24	NP_001182156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 25	ENSP00000252826.4
	TRPM4	ENST00000427978.6	TSL:1	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 24	ENSP00000407492.1
	TRPM4	ENST00000595519.5	TSL:1	n.*1619G>A		splice_region non_coding_transcript_exon	Exon 14 of 23	ENSP00000469893.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00203 AC: 510 AN: 251400 AF XY: 0.00232

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00191 AC: 2795 AN: 1461806 Hom.: 19 Cov.: 31 AF XY: 0.00209 AC XY: 1517 AN XY: 727204

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00734 AC: 633 AN: 86246

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5764

European-Non Finnish (NFE) AF: 0.00165 AC: 1832 AN: 1111958

Other (OTH) AF: 0.00225 AC: 136 AN: 60386

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74442

African (AFR) AF: 0.000554 AC: 23 AN: 41542

American (AMR) AF: 0.00451 AC: 69 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00196 Hom.: 2

Bravo AF: 0.00174

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Dec 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Nov 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPM4: BP4, BS2

TRPM4-related disorder Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hypertrophic cardiomyopathy Benign:1

Feb 22, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 25, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.18
DANN	Benign	0.39
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.84
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.052
Sift	Benign	0.35	T
Sift4G	Benign	0.38	T
Polyphen		0.029	B
Vest4		0.11
MutPred		0.21		Gain of loop (P = 0.1069)
MVP		0.41
MPC		0.34
ClinPred		0.0012	T
GERP RS		-7.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.29
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145847114; hg19: chr19-49694029;